<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Epigenetic compound screening in AML\r\nwith MNX1 overexpression"^^ . "Acute myeloid leukemia (AML) is a form of blood cancer characterized by impaired\r\ndifferentiation and accelerated proliferation due to (epi)genetic dysregulation of hematopoietic\r\nstem cells (HSC). The European LeukemiaNet (ELN) classifies AML into three subtypes:\r\nfavorable, intermediate, and unfavorable. In-house, we found that ~1.4% of AML subtypes\r\n(including deletion 7q or translocation (7;12) AML) express motor neuron and transcription factor\r\n1 (MNX1), a homeobox transcription factor (TF) known to be expressed during endoderm\r\ndifferentiation, in motor neurons and in pancreatic cells, but generally not in hematopoietic stem\r\nand progenitor cells (HSCs). MNX1-expressing AML typically belongs to the adverse\r\nsubcategories of AML. MNX1 drives leukemogenesis when overexpressed in human fetal HSCs,\r\nand these cells are transplanted into immunosuppressed mice. No therapeutic agent has been\r\nidentified yet that directly targets MNX1 or reduces MNX1 expression. Therefore, finding a\r\ncompound that either targets MNX1 or reduces MNX1 expression is essential for treating MNX1-\r\nexpressing AML cases.\r\nGDM-1 is the only AML cell line that expresses MNX1. In these cells, MNX1 is expressed when\r\na hijacked enhancer from the AHI/MYB region (chromosome 6) is juxtaposed with the MNX1\r\npromoter (chromosome 7). In my thesis, I hypothesized that epigenetic modifications could disrupt\r\nthe enhancer-promoter interaction that drives MNX1 expression. Thus, an epigenetic compound\r\nscreen was performed, and compounds that affect GDM-1 cell viability were revealed. One\r\ncompound that reduces MNX1 expression was identified. In particular, decitabine (DAC), a\r\nhypomethylating agent, emerged as a promising candidate from this screen. DAC treatment\r\nresulted in global hypomethylation and significant downregulation of MNX1 at both the RNA and\r\nprotein levels. I found that a miRNA-dependent mechanism mediates MNX1 downregulation,\r\nwhile I could rule out two miRNA-independent mechanisms, e.g. DAC mediated changes in TAD\r\nstructures in which MNX1 is embedded and the silencing via a long-noncoding RNA. miRNA-seq\r\nrevealed that miR-200a-3p, predicted to bind to the MNX1 3'UTR, is upregulated upon DAC\r\ntreatment. I validated DAC-mediated hypomethylation at the promoter region of this miRNA by\r\nlocal deep bisulfite sequencing and confirmed the interaction between miR-200a-3p and MNX1\r\n3'UTR by luciferase assay. DAC treatment in patient-derived xenografts (PDX) expressing MNX1\r\nresulted in the same phenotype, indicating the reduction of MNX1 levels through the same\r\nmechanism via upregulation of miR-200a-3p.\r\nEpigenetic therapies promise a reversible therapeutic strategy for cancer treatment. In summary,\r\nthis work focused on epigenetic-based therapies for MNX1-expressing AML and filled the gaps in\r\nthe literature regarding potential therapeutics for MNX1-expressing AML. DAC treatment\r\nreduced MNX1 via hypomethylation-mediated activation of miR-200a-3p, which targets the\r\nMNX1 3'UTR. Previous work showed the regulation of MNX1 by miR-200a and miR-141-3p in\r\nmotor neurons and pancreatic insulin-producing cells. This work demonstrated the upregulation of\r\nmiR-200a-3p in an AML cell line and PDX models and investigated the upregulation of miR-vii\r\n200a-3p upon DAC treatment in the context of AML. These results suggest the potential use of\r\nDAC or miR-200a-3p mimics against MNX1-expressing AML cases in a clinical setting."^^ . "2024" . . . . . . . "Simge"^^ . "Kelekçi"^^ . "Simge Kelekçi"^^ . . . . . . "Epigenetic compound screening in AML\r\nwith MNX1 overexpression (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "Epigenetic compound screening in AML\r\nwith MNX1 overexpression (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Epigenetic compound screening in AML\r\nwith MNX1 overexpression (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Epigenetic compound screening in AML\r\nwith MNX1 overexpression (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Epigenetic compound screening in AML\r\nwith MNX1 overexpression (Other)"^^ . . . . . . "small.jpg"^^ . . . "Epigenetic compound screening in AML\r\nwith MNX1 overexpression (PDF)"^^ . . . "1_SimgeKelekci_PhD_Thesis.pdf"^^ . . "HTML Summary of #35795 \n\nEpigenetic compound screening in AML \nwith MNX1 overexpression\n\n" . "text/html" . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .